title: Immunostimulation with macrophage-activating lipopeptide-2 increased survival in murine pneumonia.
abstract: Community-acquired pneumonia (CAP) is associated with high morbidity and mortality, and Streptococcus pneumoniae is the most prevalent causal pathogen identified in CAP. Impaired pulmonary host defense increases susceptibility to pneumococcal pneumonia. S. pneumoniae may up-regulate Toll-like receptor (TLR)-2 expression and activate TLR-2, contributing to pneumococcus-induced immune responses. In the current study, the course of severe murine pneumococcal pneumonia after pulmonary TLR-2-mediated immunostimulation with synthetic macrophage-activating lipopeptide-2 (MALP-2) was examined. Intratracheal MALP-2 application evoked enhanced proinflammatory cytokine and chemokine release, resulting in recruitment of polymorphonuclear neutrophils (PMN), macrophages, and lymphocytes into the alveolar space in WT, but not in TLR-2-deficient mice. In murine lungs as well as in human alveolar epithelial cells (A549), MALP-2 increased TLR-2 expression at both mRNA and protein level. Blood leukocyte numbers and populations remained unchanged. MALP-2 application 24 hours before intranasal pneumococcal infection resulted in increased levels of CCL5 associated with augmented leukocyte recruitment, and decreased levels of anti-inflammatory IL-10 in bronchoalveolar lavage fluid. Clinically, MALP-2-treated as compared with untreated mice showed increased survival, reduced hypothermia, and increased body weight. MALP-2 also reduced bacteremia and improved bacterial clearance in lung parenchyma, as examined by immunohistochemistry. In conclusion, pulmonary immunostimulation with MALP-2 before infection with S. pneumoniae improved local host defense and increased survival in murine pneumococcal pneumonia.
authors.affiliation: Department of Internal Medicine, Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Reppe
authors.forename: Thomas
authors.initials: T
authors.lastname: Tschernig
authors.forename: Anke
authors.initials: A
authors.lastname: Lührmann
authors.forename: Vincent
authors.initials: V
authors.lastname: van Laak
authors.forename: Karsten
authors.initials: K
authors.lastname: Grote
authors.forename: Maren V
authors.initials: MV
authors.lastname: Zemlin
authors.forename: Birgitt
authors.initials: B
authors.lastname: Gutbier
authors.forename: Holger C
authors.initials: HC
authors.lastname: Müller
authors.forename: Mischo
authors.initials: M
authors.lastname: Kursar
authors.forename: Hartwig
authors.initials: H
authors.lastname: Schütte
authors.forename: Simone
authors.initials: S
authors.lastname: Rosseau
authors.forename: Reinhard
authors.initials: R
authors.lastname: Pabst
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000150:complications / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007114:Immunization; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000382:microbiology; D055666:Lipopeptides / Q000276:immunology* / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D011018:Pneumonia, Pneumococcal / Q000150:complications / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D055666:Lipopeptides; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; C106335:macrophage stimulatory lipopeptide 2